WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau
PCX
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification ^ :
C07D 213/75, 215/38, 215/46, A61K
31/47, 31/44
Al
(11) International Publication Number: WO 94/18170
(43) International Publication Date: 18 August 1994 (18.08.94)
(21) International AppUcation Number: PCT/EP94/(X)189
(22) International Filing Date: 25 January 1994 (25.01.94)
(30) Priority Data:
9302275.4
5 February 1993 (05.02.93)
GB
(71) Applicant (for all designated States except US): SMITHKLINE
BEECHAM PLC [GB/GB]; New Horizons Court, Brentford,
Middlesex 9EP TW8 (GB).
(72) Inventors; and
(75) Inventors/Applicants (for US only): FORBES, Ian, Thom-
son [GB/GB]; SmithKline Beecham Pharmaceuticals, Cold-
harbour Road, The Pinnacles, Harlow, Essex CM19 SAD
(GB). HAM, Peter [GB/GB]; SmithKline Beecham Pharma-
ceuticals, Coldharbour Road, The Pinnacles, Harlow, Es-
sex CM19 5AD (GB). MARTIN, Roger, Thomas [GB/GB];
SmithKline Beecham Pharmaceuticals, Coldharbour Road,
The Pinnacles, Harlow, Essex CM19 SAD (GB). THOMP-
SON, Mervyn [GB/GB]; SmithKline Beecham Pharmaceu-
ticals, Coldharbour Road, The Pinnacles, Harlow, Essex
CM19 SAD (GB).
(74) Agent: GIDDINGS, Peter, J.; Corporate Intellectual Property,
SmithKline Beecham, Mundells, Welwyn Garden City,
Hertfordshire AL7 lEY (GB).
(81) Designated States: JP, US, European patent (AT, BE, CH, DE,
DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).
Published
With international search report.
(54) Title: USE OF PHENYL HETEROARYL UREAS AS 5HT2C RECEPTOR ANTAGONISTS AND UREA COMPOUNDS
(57) Abstract
2 3
The use of a compound of formula (I) or a ^
salt thereof, wherein P represents a quinoline or I |
isoquinoline residue or a 5- or 6-membered arc- '
matic heterocyclic ring contaioing up to three het- ^ ,'' ^
eroatoms selected firom nitrogen, oxygen or sul- p , ' p
phur, R' is hydrogen, Ci.* alkyl, halogen, NR^R* ^ ,
or OR'' where R', R6 and R'' are independently hy- ' - '
drogen or Ci.6 alkyl; R^ and R^ are independently
hydrogen or Ci-6 alkyl; R"* is hydrogen, Ci.* alkyl,
CF3, nitro, cyano, acyl, halogen, NR^R*, OR' or
CO2R' where R^, R* and R'' are independently hydrogen or Ci.6 alkyl as defined for R'; and n is 1, 2 or 3, in the manufacture of 1
medicament for the treatment or prophylaxis of CNS disordres.
a)
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on tiie front pages of pamphlets publishing international
applications under the PCT.
AT
Austria
GB
United Kingdom
MR
Mauritania
AU
Australia
GE
Georgia
MW
Malawi
BB
Barbados
GN
Guinea
NE
Niger
BE
Belgium
GR
Greece
NL
Netherlands
BF
Buridna Faso
HU
Hungary
NO
Norway
BG
Bulgaria
IE
Ireland
NZ
New Zealand
BJ
Benin
IT
Italy
PL
Poland
BR
Brazil
JP
Japan
PT
Portugal
BY
Belarus
KE
Kenya
RO
Romania
CA
KG
Kyrgystan
Rl)
Russian Federation
CF
Central Afiican Republic
KP
Democratic People's Republic
SD
Sudan
CG
Congo
of Korea
SE
Sweden
CH
Switzerland
KR
Republic of Korea
SI
Slovenia
CI
C5te d'lvoire
KZ
Kazakhstan
SK
Slovakia
CM
Cameroon
U
Uechtenstein
SN
Senegal
CN
Cbina
LK
Sri Lanka
TD
Chad
CS
Czechoslovakia
LU
Luxembourg
TG
Togo
CZ
Czech R^ublic
LV
Latvia
TJ
Tajikistan
DE
Germany
MC
Monaco
XT
Trinidad and Tobago
DK
Deomaik
MD
Republic of Moldova
UA
Ukraine
ES
Spain
MG
Madagascar
US
United States of America
FI
FinlaiKl
ML
MaU
uz
Uzbekistan
FR
France
MN
Mongolia
VN
Viet Nam
GA
Gabon
wo 94/18170
PCT/EP94/00189
USE OF PHENYL HETEROARYL UREAS AS 5HT2C RECEPTOR ANTAGONISTS AND UREA
COMPOUNDS
This invention relates to a method of treatment of certain CNS disorders.
5 WO 92/05170 describes cenain area derivatives which are described as possessing 5HTic
receptor antagonist activity. The 5HT j q receptor has recently been reclassified as the
5HT2C receptor fP. Hartig et al.. Trends in Pharmacological Sciences (TIPS) 1993].
Certain phenyl heteroaryl ureas known in the art have now been found to have 5HT2C
10 receptor antagonist activity. 5HT2C receptor antagonists are believed to be of potential
use in the treatment of CNS disorders such as anxiety, depression, obsessive compulsive
disorders, migraine, anorexia, Alzheimers disease, sleep disorders, bulimia, panic attacks,
withdrawal from drug abuse such as cocaine, ethanoi, nicotine and benzodiazepines,
schizophrenia, and also disorders associated with spinal trauma and/or head injury such as
15 hydrocephalus.
Accordingly, the present invention provides the use of a compound of formula (I) or a salt
thereof:
2 3
R R
wherein:
P represents a quinoline or isoquinoline residue or a 5- or 6-membered aromatic
heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or
25 sulphur;
r1 is hydrogen, Ci.g alkyl, halogen, NR5r6 or OR^ where R^, r6 and r'^ are
independently hydrogen or Cj.g alkyl;
R- and R^ are independently hydrogen or Cj.g alkyl;
r4 is hydrogen, Ci.6 alkyl, CF3, nitre, cyano, acyl, halogen, NR5r6, OR^ or C02R^
30 where R^, R^ and R'^ are independently hydrogen or C 1.5 alkyl as defined for R^ ; and
n is 1, 2 or 3,
in the manufacture of a medicament for the treatment or prophylaxis of CNS disorders.
wo 94/18170
PCT/EP94/00189
Ci.galkyl groups, whether alone or as part of another group, can be straight chain or
branched.
5 Prefsiably R ^ is hydrogen or methyl.
Preferably and r3 are hydrogen.
Suitable moieties when the ring P is a 5- or 6-membered aromadc heterocyclic ring
10 include pvnridyl, pyrazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, thiadiazolyl
and triazolyl. Preferably P is pyridyl attached to the urea nitrogen at position 3 or 4; or P
is quinoline attached to the urea nitrogen at posinon 3, 4 or 6, preferably at posirion 4.
Preferably n is 1 or 2. When n is greater than 1, the R'^ groups can be the same or
15 different. Preferably the phenyl ring is mono-subsntuted and R^ is CF3 or -NMe2
(preferably in the meta position); -OMe, (preferably in the meta or para position); C02Et
(preferably in the meta position) or the phenyl ring is preferably di substituted with meta
chloro and para methyl.
20 Preferred compounds of formula (I) include:
N-(Phenyl)-N'-(2-methyl-4-quinolinyl) urea,
N-(6-Quinolinyl)-N'-(3-trifluoromethylphenyl) urea,
N-(3-Dimethylaminophenyl)-N'-(6-quinolinyl) urea,
N-(Phenyl)-N'-(6-quinolinyl) urea,
25 N-(4-Methoxyphenyl)-N'-(2-methyl-4-quinolinyl) urea,
N-(3-Dimethylaminophenyl)-K-(2-methyl-4-quinolinyl) urea,
N-(3-Methoxyphenyl)-N'-(2-methyl-4-quinolinyl) urea,
N-(3-Ethoxycarbonylphenyl)-N -(2-melhyl-4-quinolinyl) urea,
N-(2-Methyl-4-quinolinyl)-N'-(3-trifluoromethylphenyl) urea ,
30 N-(Phenyl)-N'-(3-quinolinyl) urea,
N-(3-Chloro-4-methylphenyI)-N'-(3-pyridyl) urea,
N-(3-Chloro-4-methylphenyl)-N'-(4-pyridyl) urea,
N-(3-Pyridyl)-N'-(3-(trifluoromethyl)phenyl)urea,
N-(3-Methylphenyl)-N'-(3-pyridyl)urea,
35 N-(4-Chlorophenyl)-N'-(3-pyridyl)urea,
N-(3-Chlorophenyl)-N'-(3-pyridyl)urea,
N-(3-Hydroxyphenyl)-N'-(2-methyl-4-quinoliny])urea,
N-(3-Bromophenyl)-N'-(3-pyridyl)urea,
wo 94/18170
PCT/EP94/00189
N-(3,4-Dichlorophenyl)-N'-(3-pyridyl)urea,
N-(3-Fluoro-4-methylphenyl)-N'-(3-pyridyl)urea,
N-(4-Ethoxycarbonylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-methoxycarbonylphenyl)-N'-(3-pyridyl)urea,
5 N-(3-Bromo-4-methylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-cyanophenyl)-N'-(3-pyridyl)urea,
N-(4-Nitro-3-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(4-Chloro-3-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-carboxyphenyl)-N'-(3-pyridyl)urea,
10 N-(2-Methoxy-4-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-ethylphenyl)-N'-(3-pyridyl)urea,
N-C3-Chloro-4-propylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-tert-butylphenyl)-N'-(3-pyridyl)urea,
N-(3-Hydroxy-4-(methoxycarbonyl)phenyl)-N'-(3-pyridyl)urea
15 or a pharmaceutically acceptable salt thereof.
The compounds of the formula (I) can form acid addinon salts with acids, such as
conventional pharmaceutically acceptable acids, for example maleic, hydrochloric,
hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and
20 methanesulphonic. Compounds of formula (I) may also form N-oxides or solvates such as
hydrates, and the invention also extends to these forms.
Certain compounds of formula (I) may exist tautomerically in more than one form. The
invention extends to these and any other tautomeric forms and mixtures thereof.
25 Certain compounds of formula (I) are capable of existing in stereoisomeric forms
including enantiomers and the invention extends to each of these stereoisomeric forms and
to mixtures thereof including racemates. The different stereoisomeric forms may be
separated one from the other by the usual methods, or any given isomer may be obtained
by stereospecific or asymmetric synthesis.
30
Cenain compounds of formula (I) are novel and form a further aspect of the invention.
Panicularly preferred novel compounds include those listed above and exemplified herein.
The invention further provides a method of treatment or prophylaxis of CNS disorders, in
35 particular anxiety, depression, migraine, anorexia, obsessive compulsive disorders,
Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse,
schizophrenia and/or disorders associated with spinal trauma and/or head injuries (in
panicular anxiety and depression) in mammals including humans, which comprises
wo 94/18170
PCT/EP94/00189
administenng to the sufferer a therapeutically effective amount of a compound of formula
(I) or a pharmaceutical ly acceptable salt thereof.
The invention also provides novel compounds of formula (I) or a pharmaceutically
5 acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or
prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders,
Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse,
schizophrenia and/or disorders associated with spinal trauma and/or head injuries.
10 The present invention also provides a pharmaceutical composition, which comprises novel
compounds of formula (I) or a pharmaceudcally acceptable salt thereof, and a
pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture,
15 suitably at ambient temperature and atmospheric pressure, is usually adapted for oral,
parenteral or rectal administration and, as such, may be in the form of tablets, capsules,
oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable
or infusable solutions or suspensions or suppositories. Orally administrable compositions
are generally preferred.
20
Tablets and capsules for oral administration may be in unit dose form, and may contain
conventional excipients, such as binding agents, fillers, tabletring lubricants, disintegrants
and acceptable wetting agents. The tablets may be coated according to methods well
known in normal pharmaceutical practice.
25
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension,
solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for
reconstiturion with water or other suitable vehicle before use. Such liquid preparations
may contain conventional additives such as suspending agents, emulsifying agents,
30 non-aqueous vehicles (which may include edible oils), preservatives, and, if desired,
conventional flavourings or colourants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound
of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The
35 compound, depending on the vehicle and concentration used, can be either suspended or
dissolved in the vehicle. In preparing solutions, the compound can be dissolved for
injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents
wo 94/18170
PCT/EP94/00189
are dissolved in the vehicle. To enhance the stability, the composition can be frozen after
filling into the vial and the water removed under vacuum. Parenteral suspensions are
prepared in substantially the same manner, except that the compound is suspended in the
vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
5 The compound can be sterilised by exposure to ethylene oxide before suspension in a
sterile vehicle. Advantageously, a surfactant or wetting agent is included in the
composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by
10 weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary
in the usual way with the seriousness of the disorders, the weight of the sufferer, and other
.similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg,
15 more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be
administered more than once a day, for example two or three a day, so that the total daily
dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a
number of weeks or months.
20 When administered in accordance with the invention, no unacceptable toxicological effects
are expected with the compounds of the invention.
The present invention also provides a process for the preparation of a compound of
formula (I) or a pharmaceutically acceptable salt thereof, which process comprises
25
the coupling of a compound of formula (II);
R ^P^ A (II)
30 with a compound of formula (III);
4'
(III)
35 wherein P is as defined in relation to formula (I), A and B contain the appropriate
functional group(s) necessary to form the moiety, -NR^'CONR^' when coupled, the
- 5 -
wo 94/18170
PCT/EP94/00189
variables . R^', r3\ and R^^' are R^ R^, r3, and r4 respectively, as defined in
formula (I), or groups convenible thereto, and thereafter optionally and as necessary and
in any appropriate order, convening any R ^ , , r3 and R'* , when other than R^, r2,
r3 and respectively to R^, r3 and R'^, interconvening R ^ R^. r3, and R"^ and
5 forming a pharmaceudcally acceptable salt thereof.
Suitable examples of groups A and B include:
(i) A is -N=C=0 and B is -NHR3',
10 (ii) A is -NR2'cOL and B is -NHR3',
(iii) A is -NHR2' and B is NR^'COL,
(iv) A is NHR2' and B is -N=C=0 or
(v) A is halogen and B is -NR^'CONHR^'
15 wherein R-^ and R^' are as defined above and L is a leaving group. Examples of suitable
leaving groups L include halogen such as chloro, bromo, imidazole or phenoxy or
phenylthio optionally subsntuted for example with halogen.
When A is -N=C=0 and B is NHR3' or when A is NHR^' and B is -N=C=0 the reaction is
20 suitably carried out in an inert solvent for example dichloromethane or toluene at ambient
temperature. When A is -NR^'COL and B is NHR^' or when A is -NHR^' and B is
-NR3'cOL, the reaction is suitably carried out in an inert solvent such as dichloromethane
at ambient temperature optionally in the presence of a base, such as triethylamine or in
dimethylformamide at ambient or elevated temperature. When A is halogen and B is
25 NR3'c0NHR2' , the reacdon is suitably carried out in an inert solvent such as toluene at
elevated temperature, optionally in the presence of a base.
Suitable examples of groups R^ and R'^ , which are convertible to R^ and R^ alkyl groups
respectively, include acyl groups which are introduced conventionally and may be
30 convened to the corresponding alkyl group by conventional reduction, such as using
sodium borohydride in an inen solvent followed by hydrogenolysis in an inert solvent.
Hydrogen substituents may be obtained from alkoxycarbonyl groups which may be
convened to hydrogen by hydrolysis and decarboxylation.
35 Interconversions of R ' , R^, r3 and R'* are carried out by conventional procedures.
For example, in the case wherein R^ is C].^ alkyl and r3 is hydrogen it is possible to
introduce a Cj.g alkyl group at the r3 position by conventional alkylation using 1 molar
equivalent of a Cj.g alkyl halide and 1 molar equivalent of a suitable base in an inert
solvent. Suitable examples of a group R^' and r3' which is convertible to and r3,
-6-
wo 94/18170 PCT/EP94/00189
include alkoxycarbonyl and benzyl or /jora-methoxybenzyl which are converted to r2
and is hydrogen using conventional conditions.
r1 halo and R'* halo may be introduced by selective halogenation of the ring P or the
5 benzene ring respecdvely using conventional condinons.
It should be appreciated that it may be necessary to protect any R^ to R^ hydrogen
variables which are not required to be inierconverted. Suitable protecting groups are
described in 'Protective groups in organic synthesis' Greene T.W., New York, Wiley
10 (1981). It should be appreciated that it is preferred that groups R^ to R^ are introduced
before coupling compounds of formula (II) and (III).
Compounds of formula (II) in which A is NHR^' are known compounds or can be
prepared analogously to known compounds, see, for example, WO 92/05170 (SmithKline
15 Beecham pic). Compounds of formula (II) in which A is -N=C=0 may be prepared by
treating a compound of formula (11) in which :
i) A is amino, with phosgene or a phosgene equivalent, in the presence of excess base
in an inen solvent.
20 ii) A is acylazide (i.e. CON3), via the nitrene, by thermal rearrangement using
conventional conditions (ref L.S. Trifonov et al, Helv. Chim. Acta 1987 262).
iii) A is CONH2, via the nitrene intermediate using conventional conditions.
Examples of phosgene equivalents include triphosgene, carbonyldiimidazole, phenyl
25 chloroformate and phenyl chorothioformate. Compounds of formula (II) in which A is
NR2'C0L may be prepared by reacting a compound of formula (II) in which A is NHR2'
with phosgene or a phosgene equivalent in an inert solvent, at low temperature, if
necessary in the presence of one equivalent of a base such as trithylamine. Compounds of
formula (II) in which A is halogen and R4' is hydrogen are commercially available.
30
Compounds of formula (HI) are commercially available or may be prepared according to
analogous methods to those outlined above for compounds of formula (II).
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the
35 appropriate acid or acid derivative. N-oxides may be formed conventionally by reaction
with hydrogen peroxide or percarboxylic acids.
The following Examples illustrate the preparation of compounds of the invention.
wo 94/18170
PCT/EP94/00189
Example 1
N-(Phenyl)-N'-(2-methyl-4-quinolinyl) urea
To a solution of 2-methyl-4-amino-quinoline (1.58g; lO.OmM) in ethanol free chloroform
5 (70 ml) at lOom temperature was added dropwise phenyl isocyanate (1.4 ml, 12.0 mM) in
dry toluene (25 ml) over a period of 5 minutes. The whole was then stirred at room
temperature for 1 8h followed by heating under reflux for 2h. After cooling to room
temperature ethanol (20 ml) was added and after an additional Ih the solvent was removed
under reduced pressure to give an oil. The oil was treated with ether (50 ml) to give an off
10 white solid which was crystallised from ethyl acetate to give the title compound (El)
(1.37g, 60%) as a white solid, m.p. 201-3°C.
NMR (D6-DMSO) 5: 2.10 (3H,s), 7.05 (lH,t,J=7Hz), 7.36 (2H,t, J=7Hz), 7.47-7.64
(3H,m), 7.70 (lH.t,J=7Hz), 7.89 (lH,d.J=7Hz), 8.08-8.20 (2H,m), 9.15 (IH, broad s),
15 9.39 (IH, broad .s).
Found: C, 73.74; H, 5.44; N, 15.29%
C17H15N3O requires: C, 73.63; H, 5.45; N, 15.15%
Example 2
20 N-(6-QuinoHnyl)-N'-(3-trifluoromethylphenyI) urea hydrochloride
The title compound was prepared in 87% yield from 3-trifluoromethyl phenyl isocyanate
and 6-aminoquinoline following a procedure similar to that in Example 1. Free base
precipitated from the reaction mixture within a total of 3h at room temperature and was
25 converted to the hydrochloride salt using hydrogen chloride in ether/ethanol.
m.p. 208-1 3°C •
NMR (D6-DMS0) 5: 7.33-7.50 (lH,m), 7.54-7.85 (2H,m), 7.95-8.28 (3H,m), 8.49
(lH,d,J=8Hz), 8.60-8.75 (lH,m), 9.05-9.30 (2H,m), 10.19 (lH,s). 10.40 (lH,s).
30 Found: M+ 331.0917 C17H12F3N3O requires 331.0964
Example 3
N-(3-Dimethylaminophenyl)-N'-(6-quinolinyl) urea dihydrochloride
35 To a solution of carbonyl diimidazole (0.40g, 2.47 mM) in dichloromethane (5 ml) was
added 3-dimethylamino aniline (0.37g, 2.26 mM) in dichloromethane (5 ml). After
stirring at room temperature for 0.5h, the solution was evaporated to dryness. The residue
was taken up in dimethylformamide (5ml) and to this solution was added 6-amino
wo 94/18170
PCT/EP94/00189
quinoline (0.36g, 2.50 mM) in dimethylformamide (5 ml). The reaction mixture was
heated to 90°C for Ih, then cooled and added dropwise to water with vigorous stirring.
Later the solution was collected to give the crude product (0.65g) which was converted to
the hydrochloride salt (E3) using hydrogen chloride in ether/ethanol (C 29g, 36%).
5 m.p. 185-90°C.
NMR (Dg-DMSO) 6: 3.09 (6H,s), 7.02-7.20 (lH,m), 7.21-7.49 (2H,m), 7.71 (IH, broad
s), 7.90-8.15 (2H,m), 8.33 (lH,dJ=9Hz), 8.51-8.61 (lH,m), 9.02-9.18 (2H,m), 9.90 (IH,
broad s), 10.39 (IH, broad s).
10 Found: 306.1465 Ci8HigN40 requires: 306.1516
Example 4
N-(phenyl)-N'-(6-quinolinyl) urea
15 The title compound (E4) was prepared in 56% yield from 6-aminoquinoline and
phenylisocyanate following a procedure similar to that in Example 1. Free base
precipitated from the reaction mixture and was recrystallised from ethanol.
NMR (D6-DMSO) 5: 7.0 (lH,t,6Hz), 7.30 (2H,t,6Hz), 7.42-7.53 (3H,m), 7.71 (IH, dd,
20 6Hz,3Hz), 7.94 (lH,d,J=6Hz), 8.19 (lH,d,j=3Hz), 8.24-8.28 (lH,m), 8.71-8.77 (lH,m),
8.82 (lH,s), 9.08 (lH,s).
Example 5
N-(4-MethoxyphenyI)-N'-(2-methyl-4-quinoIinyl) urea
25
4-Methoxyphenyl isocyanate (0.82 ml, 6.3 mmol), in dry dichloromethane (30 ml) was
added slowly to 4-aminoquinaldine (1 g, 6.3 mmol) in dry toluene (30 ml) under a
nitrogen atmosphere. This was refluxed for 2.5h, then left at room temperature for 19h.
The precipitate which formed was filtered off, washed with cold 1:1
30 toluene/dichloromethane and dried in vacuo. The crude product was chromatographed on
silica gel using dichloromethane as the eluant to give the title compound (1.31 g, 68%) as
a white solid, m.p. 180-185°C.
35
NMR (D^-DMSO) 5:
2.59 (3H, s), 3.75 (3H, s), 6.93 (2H, m), 7.44 (2H, m), 7.6
(IH, t, J 6), 7.71 (IH, t, J 6), 7.89 (IH, d, J 8),8.13 (2H, m),
9.11 (lH,s), 9.17 (lH,s)
wo 94/18170
PCT/EP94/00189
Found: C, 70.32; H, 5.67; N, 13.44 7o
C18H17N3O2 requires C. 70.34; H. 5.58; N. 13.67%
Found: M+ 307 C]gHi7N302 requires 307
5 Example 6
N-(3-Dimethylaminophenyl)-N -(2-methyl-4.quinonnyl) urea
l,r-Carbonyldiimidazole (0.26g, 1.6 mmol), was added portionwise to a solution of 4-
aminoquinaldine (0.23g, 1.47 mmol) in dry dichloromethane (15 ml), under a nitrogen
10 atmosphere. After l/2h, at room temperature, the solvent was evaporated off and the
residue was taken up in DMF (5 ml). After addition of 3-(dimethylamino)aiiiline (0.2g,
1.47 mmol) in DMF (10ml), the reaction mixture was heated at 90°C for Ih. Addition of
water after cooling to room temperature, gave the crude product as a precipitate, which
was collected and dried in vacuo. Purification by column chromatography on silica gel,
15 using dichloromethane as eluant gave the title compound (0.1 6g, 34%) as a light brown
solid, m.p. 167- 171 °C.
NMR (D6-DMSO) 5: 2.6 (3H, s), 2.91 (6H, s), 6.42 (IH, m), 6.77 (IH, m), 6.98
Found: M+ 320 C19H20N4O requires 320
Example 7
N-(3-Methoxyphenyl)-N'-(2-methyl-4-quinolinyl) urea
25
3-Methoxyphenyl isocyanate (0.83 ml, 6.3 mmol) in dry dichloromethane (30 ml) was
added slowly to 4-aminoquinaldine (Ig, 6.3 mmol) in dry toluene (30 ml) under a nitrogen
atmosphere, and left to stir at room temperature for 19h. The precipitate which formed
was filtered off, washed with cold 1 : 1 toluene/dichloromethane and dried in vacuo. The
30 crude product was purified by recrystallization from ethanol to give the title compound
(0.99g, 51%) as a white solid, m.p. 191-193°C.
20
(IH. s), 7.12 (IH, t, J 6), 7.59 (IH, t, J 3), 7.72 (IH, t, J 6),
7.89 (IH, d, J 6), 8.12 (2H, m), 9.10 (IH, s), 9.19 (IH, s).
35
NMR (D6-DMSO) 5:
2.6 (3H, s), 3.77 (3H, s), 6.62 (IH, m), 6.99 (IH, d, J 6),
7.22-7.28 (2H, m), 7.61 (IH, t, J 3), 7.72 (IH, t, J 3), 7.89
(IH, d, J 6), 8.14 (2H, m), 9.18 (IH, s), 9.35 (IH, s).
Found: M+ 307 Ci8H]7N302 requires 307
- 10 -
wo 94/18170
PCT/EP94/00189
Example 8
N-(3-Ethoxycarbonylphenyl)-N'-(2-methyl-4-quinolinyl) urea
5 3-Ethoxycarbonylphenyl isocyanate (Ig, 5.2 mmol) in dry dichloromethane (30 ml), was
added slowly to 4-aminoquinaldine (0.83g, 5.2 mmol) in dry toluene (30 ml), under a
nitrogen atmosphere, and left to stir at room temperature for 19h. The precipitate which
formed was filtered off, washed with cold 1:1 toluene/dichloromethane and dried in
vacuo. The crude product was chromatographed on silica gel, using dichloromethane as
10 the eluant to give the tide compound (0.78g, 43%) as white crystals, m.p. 165-170°C.
NMR (D6-DMSO) 5: 1.32 (3H, t, J 3), 2.6 (3H, s), 4.33 (2H, q, J 6), 7.48 (IH, t, J
6), 7.59-7.75 (4H, m), 7.9 (IH, d, J 6), 8.12 (2H, m), 8.22
(IH, s),9.18(lH, s), 9.57 (IH, s).
1 5 Found: M+ 349 C20H ] 9N3O3 requires 349
Example 9
N-(2-Methyl-4-quinolinyl)-N'-(3-tinuoromethylphenyl) urea
20 a,a,a- Trifluoro-m-tolyl isocyanate (0.96 ml, 6.33 mmol) in dry dichloromethane (30 ml)
was added slowly to 4-amino-quinaldine (Ig, 6.33 mmol) in dry toluene (30 ml), under a
nitrogen atmosphere. Following the procedure described in Example 4, gave the title
compound (0.1 8g, 85%) as a white powder, m.p. 165-170°C.
25 NMR (Dg-DMSO) 6: 2.58 (3H, s), 7.37 (IH, m), 7.55-7.61 (3H, m), 7.7 (IH, t J
6), 7.87 (IH, d, J 8), 8.10 (3H, m), 9.22 (IH, s), 9.60 (IH,
s).
Found: M+ 345 C]gHi4N30 F3 requires 345
30 Example 10
N-(Phenyl)-N'-(3-quinolinyI) urea
Phenyl isocyanate (0.75 ml, 7 mmol) in dry dichloromethane (30 ml) was added slowly to
3 aminoquinoline (Ig, 7 mmol) in dry toluene (30 ml) under a nitrogen atmosphere.
35 Following the procedure described in Example 7, gave the title compound (1.18g, 65%) as
a white powder, m.p. 289-290°C.
- 11 -
wo 94/18170
PCT/EP94/00189
NMR (Dg-DMSO) 5: 7.0 (IH, t. J 6), 7.30 (2H, t, J 8), 7.49-7.61 (4H, m),
7.88-7.97 (2H, m), 8.54 (IH, d, J 3), 8.82 (IH, d, J 3), 8.92
(IH, s),9.14(lH, s).
5 Found: C. 72.78; H, 5.13; N, 15.98%
C16H13N3O requires C, 72.99; H, 4.98; N, 15.96%
Found: M+ 263 C16H13N3O requires 263
Example 1 1
10 N-(3-Chloro-4-methylphenyl)-N'-(3-pyridyl) urea hydrochloride
Nicotinoyl azide (0.40g, 2.7 mmol) was stirred at reflux under nitrogen atmosphere in dry
toluene (10 ml) for Ih, with gas evolution. The soludon was cooled to ambient
temperature, and 3-chloro-4-methylaniIine (0.30 ml, 2.4 mmol) was added. The
15 suspension so formed was stirred for 1 h, when the solid was filtered off, washed with 1 : 1
toluene/dichloromethane, and dried in vacuo at 70°C. This gave the free base of the title
compound ('0.64g, 85%) as a white solid.
NMR (D6-DMS0) 5: 2.25 (3H, s), 7.23 f2H, m), 7.31 (IH, m), 7.70 (IH, s), 7.93
20 (IH, m,), 8.18 (IH, d, J 4), 8.59 (IH, d, J 2), 8.90 (2H, 2xs).
N-(3-Chloro-4-methyl)-N'-(3-pyridyl) urea (0.55g, 2.1 mmol) was dissolved in hot ethanol
(10 ml), and a solution of hydrogen chloride in ether (ca. 0.9M, 2.5 ml, ca. 2.3 mmol) was
added. The suspension was cooled to ambient temperature, and the solid was filtered off,
25 washed with cold ethanol, and dried in vacuo at 70°C. This gave the title compound
(0.62g, 76%) as a white solid, m.p. 214.5-21 6°C.
NMR (D6-DMS0) 5: 2.25 (3H, s), 7.25 (2H, m), 7.68 (IH, s), 7.92 (IH, dd, J 8,
5), 8.33 (IH, d, J 8). 8.49 (IH, d), 9.07 (IH, s), 9.79 (IH, s),
30 10.37 (IH, s).
Found: C, 51.4; H, 4.5; N, 14.5%
C13H12CIN3O. HCl. O.25H2O requires C, 51.6; H, 4.5; N, 13.9%
Found: M+ 261, 263. C13H12CIN3O requires 261,263.
35 Example 12
N-(3-Chloro-4-methylphenyl)-N'-(4-pyridyl) urea hydrochloride
?-Chloro-4-methylaniline (0.65 ml, 5.3 mmol) was stirred under nitrogen in
- 12-
wo 94/18170
PCT/EP94/00189
dichloromethane (15 ml) at 0°C as trieihylamine (0.82 ml, 5.9 mmol) was added. To this
mixture was then added phosgene in toluene solution (1.93M, 4.1 ml, 7.9 mmol). After
stirring at 0°C for 0.5h, triethylamine (1.6 ml, 11. 8 mmol) was added and, after a further
0.5h, 4-aminopyridine (0.50g, 5.3 mmol) w^s added. The mixture was stirred at ambient
5 temperature for 16h, and then treated with sodium hydroxide solution (5M, ca. 1 ml).
After 0.5h, it was diluted with water (50 ml) and dichloromethane (50 ml), and the
precipitate was filtered off, washed with water, and dried in vacuo at 70°C. This gave the
free base of the title compound (l.OSg, 74%) as a white solid.
10 NMR (D6-DMSO) 5: 2.25 (3H, s), 7.23 (2H, m), 7.41 (2H, d, J 5), 7.67 (IH,
s),8.35 (2H, d, J 5) 8.99 (IH, s), 9.18 (IH, s).
N-(3-Chloro-4-methylphenyl)-N'-(4-pyridyl) urea (1.03g, 3.9 mmol) was treated with
hydrogen chloride using the method of Example 11. This gave the tide compound (0.95g,
15 8 1 %) as a white solid, m.p. 235-240°C (decomp.).
NMR (D^-DMSO) 5: 2.27 (3H, s), 7.28 (2H, m), 7.67 (IH, s), 7.89 (2H, d, J 6),
8.60 (2H, d,J6), 10.09 (IH, s), 11.27 (IH, s).
Found: C, 50.6; H, 4.4; N, 13.7%
20 C13H12CIN3O.HCI . 0.59 H2O requires C, 50.6; H, 4.6; N, 13.6%
Found: M+ 261,263 C13H12CIN3O requires 261, 263.
Example 13
N-(3-Pyridyl)-N'-(3-(trifluoromethyI)phenyI)urea
25
The tide compound was prepared in 91% yield from 3-pyridyl isocyanate and 3-
aminobenzotrifluoride; m.p. 180-184° C.
NMR (DMSO-d6) 5: 7.3 (2H, m), 7.55 (2H, m), 7.95 (IH, d, J 8), 8.0 (IH, s), 8.2 (IH, d,
30 J 4), 8.6 (IH, d, J 2), 9.0 (IH, s), 9.2 (IH, s).
Example 14
N-(3-Methylphenyl)-N'-(3-pyridyl)urea hydrochloride
35 The tide compound was prepared in 87% yield from 3-aminopyridine and m-tolyl
isocyanate. followed by salt formarion with HCl; m.p. 182-183° C.
NMR (DMSO-d6) S: 2.3 (3H, s), 6.85 (IH, d, J 7), 7.2 (IH, t, J 8), 7.3 (2H, m), 7.9 (IH,
dd, J 8,5), 8.3 (IH, m), 8.5 (IH, d, J 5), 9.1 (IH, d, J 2), 9.5 (IH, s), 10.35 (IH, s).
- 13 -
wo 94/18170
PCT/EP94/00189
Example 15
N-(4-Chlorophenyl)-N'-(3-pyridyl)urea
5 The title comnound was prepared in 29% yield from 3-aminopyridine, 1,1'-
carbonyldiimidazole and 4-chioroaniline: m.p. 207-209° C
NMR (DMSO-d6) 5: 7.3 (3H, m), 7.5 (2H, d, J 9), 7.95 (IH, m), 8.2 (IH, m), 8.6 (IH, d,
J 2), 8.9 (IH, s), 9.0(1H, s)
10
Example 16
N-(3-Chlorophenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 86% yield from 3-aminopyridine and 3-chlorophenyI
1 5 isocyanate; m.p. 1 85- 1 87° C
NMR fDMSO-d6) 5: 7.0 (IH, m), 7.3 (3H, m), 7.7 (IH, s), 7.95 (IH. m), 8.2 (IH, m),
8.6 (IH, d, J 2), 8.95 (IH, s), 9.05 (IH, s)
20 Example 17
N-(3-Hydroxyphenyl)-N'-(2-methyl-4-quinolinyl)urea
The title compound was prepared in 19% yield from 4-amino-2-methylquinoline, 1,1'-
carbonyldiimidazole and 3-aminophenol; m.p. 224-225° C
25
NMR (DMSO-d6) 5: 2.6 (3H, s), 6.45 (IH, m), 6.9 (IH, d, J 7), 7.1 (2H, m), 7.6 (IH, t, J
7), 7.7 (IH, t, J 7), 7.9 (IH, d, J 7), 8.15 (2H, m), 9.2 (IH, b), 9.3 (IH, s), 9.45 (IH, s)
Example 18
30 N-(3-Bromophenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 75% yield from 3-bromopyridine and 3-pyridyl
isocyanate; m.p. 190-193° C.
35 NMR (DMSO-d6) 5: 7.10-7.40 (4H, m), 7.86 (IH, s), 7.94 (IH, m), 8.22 (IH, d, J=5Hz),
8.62 (IH, d, J=2Hz), 8.93 (IH, s), 9.02 (IH, s).
Example 19
N-(3,4-Dichlorophenyl)-N'-(3-pyridyI)urea
40
The tide compound was prepared in 65% yield from 3,4-dichloroaniline and 3-pyridyl
isocyanate; m.p. 206° C-210° C.
NMR fDMSO-D6) 8: 7.25-7.42 (2H, m), 7.50 (IH, d, J=7Hz), 7.83-7.90 (2H, m), 8.23
45 (IH, d, J=3Hz), 8.62 (IH, d, J=lHz), 8.98 (IH, s), 9.23 (IH, s)
- 14 -
wo 94/18170
PCT/EP94/00189
Example 20
N-(3-Fluoro-4-methyiphenyl)-N'-(3-pyridyl)urea
5 The title compound was prepared in 85% yield from 3-fluoro-4-methylaniline and 3-
pyridyl isocyanate; m.p. 190-191° C.
NMR (DMSO-D6) 6: 7.02-7.48 (4H, m), 7.94 (IH, m), 8.19 (IH, m), 8.59 (IH, m), 8.87
(IH, s), 8.92 (IH, s)
10
Example 21
N-(4-Ethoxycarbonylphenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 83% yield from ethyl 4-aminobenzoate and 3-pyridyI
15 isocyanate: m.p. 156-160° C
NMR (DMSO-Dg) 6: 1.32 (3H, t, J=7.5Hz), 4.30 (2H, q, J=7.5Hz), 7.34 (IH, dd, J=7Hz
& 4Hz), 7.60 (2H, m), 7.86-8.02 (3H, m), 8.21 (IH, m), 8.63 (IH, m), 8.96 (IH, s), 9.24
(IH, s)
20
Example 22
N-(3-Chloro-4-methoxycarbonylphenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 30% yield from methyl 4-amino-2-chlorobenzoate
25 and 3-pyridyl isocyanate m.p. 170-171° C
NMR (DMSO-Dg) 5: 3.82 (3H, s), 7.30 (2H, m), 7.78-8.00 (3H, m), 8.25 (IH, m), 8.64
(IH, m), 9.08 (IH, s), 9.39 (IH, s)
Example 23
N-(3-Bromo-4-methylplienyl)-N'-(3-pyridyl)urea
The title compound was prepared in 61% yield from 3-bromo-4-methylaniline and 3-
pyridyl isocyanate; m.p. 168-171° C
NMR (DMSO-D6) 6: 2.28 (3H, s), 7.21-7.39 (3H, m), 7.83-8.00 (2H, m), 8.20 (IH, m),
8.61 (lH,m), 8.89 (2H, m)
Example 24
40 N-(3-Chloro-4-cyanophenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 22% yield from 4-amino-2-chlorobenzonitrile and 3-
pyridyl isocyanate; m.p. 262-264° C
30
35
- 15 -
wo 94/18170
PCT/EP94/00189
NMR (DMSO-D6) 5: 7.28-7.56 (2H. m), 7.80-8.06 (3H. m), 8.26 (IH, m), 8.64 (IH, s),
9.17 (IH. s), 9.54 (IH, s)
Example 25
5 N.(4-Nitro-3-trifluoromethylphenyl)-N'-(3-pyridyI)urea
The title compound was prepared in 31% yield from 4-nitro-3-trifloromethylaniline and 3-
pyridyl isocyanate; m.p. 214-216° C
10 NMR (DMSO-D6) 5: 7.37 (IH, dd, J=7Hz & 4Hz), 7.87 (IH, m, J=7Hz), 7.97 (IH, m,
J=7Hz), 8.14-8.29 (3H, m), 8.67 (IH, m), 9.22 (IH, s), 9.81 (IH, s)
Example 26
N-(4.Chloro-3-trifluoromethyiphenyI)-N'-(3-pyridyl)urea
15
The title compound was prepared in 48% yield from 4-chloro-3-trifluoromethylaniline and
3-pyridyl isocyanate: m.p. 196-199° C.
NMR (DMSO-D6) 5: 7.33 (IH, dd, J=7Hz & 4Hz), 7.59-7.71 (2H, m), 7.95 (IH, m),
20 8.10(1H, m), 8.22 (lH,m), 8.63 (lH,m), 9.04 (lH,s), 9.32 (lH,s)
Example 27
N-(3-Chloro-4-carboxyphenyl)-N'-(3-pyridyI)urea
25 The title compound was prepared in 86% yield from 4-amino-2-chlorobenzoic acid and 3-
pyridyl isocyanate; m.p. 170-175° C
NMR (DMSO-D6) 5: 7.41 (2H, m), 7.76-7.88 (2H, m), 7.99 (IH, d, J=7Hz), 8.25 (IH,
br s), 8.68 (IH, br s), 9.13 (IH, s), 9.37 (IH, s)
30
Example 28
N-(2-Methoxy-4-trifluoromethyIphenyl)-N'-(3-pyridyl)urea
The tide compound was prepared in 91% yield from 2-methoxy-4-trifluoromethyl-aniline
35 and 3-pyridyl isocyanate; m.p. 210° C
NMR (DMSO-D6) 5: 4.00 (3H, s), 7.16-7.45 (3H, m), 7.98 (IH, m, J=7Hz), 8.23 (IH,
m), 8.48-8.74 (3H, m), 9.60 (IH, s)
40 Example 29
N-(23-Dichlorophenyl)-N'-(2-methyl-4-quinolinyI)urea
The title compound was prepared in 22% yield from 2,3-dichloroaniline and 2-methyl-4-
quinolinyl isocyanate; m.p. 125-127° C
45
- 16-
wo 94/18170
PCT/EP94/00189
NMR (DMS0-D6) 5: 2.62 (3H. s), 7.34-7.46 (2H, m), 7.63 (IH, t, J=7Hz), 7.76 (IH, t,
J=7Hz), 7.94 CIH, t, J=7Hz), 8.12-8.31 (3H, m), 9.27 (IH, s), 9.83 (IH, s)
Example 30
5 N.(3-Chloro-4-pthylphenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 85% yield from 3-chloro-4-ethylaniiine & 3-pyridyl
isocyanate; m.p. 193-196° C.
10 NMR (DMSO-d6) 5: 1.16 (3H, t, J=5Hz), 2.64 (2H, q, J=5Hz), 7.20-7.40 (3H, m), 7.67
(IH, s), 7.94 (IH, m), 8.20 (IH, d, J=2Hz), 8.60 (IH, d, J=0-lHz), 8.90 (2H, d, J=5Hz).
Example 31
N-{3-Chloro-4-propylphenyl)-N'-(3-pyridyl)urea
15
The title compound was prepared in 78% yield from 3-Chloro-4-propylaniline & 3-pyridyl
isocyanate; m.p. 184-186° C
NMR (DMS0-D6) 6: 0.91 (3H, t, J=5Hz), 1.56 (2H, q, J=5Hz), 2.60 (2H, t, J=5Hz),
20 7.20-7.35 (3H, m), 7.68 (IH, s), 7.94 (IH, m), 8.19 (IH, d, J=2Hz), 8.59 (IH, d, J=0-
IHz), 8.92 (2H, d, J=5Hz).
Example 32
N-(3-Chloro-4-tert-butylphenyl)-N'-(3-pyridyl)urea
25
The title compound was prepared in 73% yield from 3-chloro-4-tert-butylaniline & 3-
pyridyl isocyanate; m.p. 190° C-193° C.
NMR (DMSO-D6) 5: 1.42 (9H, s), 7.20-7.40 (3H, m), 7.66 (IH, d, J=2Hz), 7.93 (IH,
30 m), 8.19 (IH, d, J=5Hz), 8.60 (IH. d, J=2Hz), 8.90 (2H, d, J=l IHz)
Example 33
N-(3-Hydroxy-4-(methoxycarbonyl)phenyl)-N'-(3-pyridyl)urea
35 N-(3-Hydroxy-4-carboxyphenyl)-N'-(3-pyridyl)urea was prepared in 69% yield from 4-
aminosalicylic acid and 3-pyridyl isocyanate in DMF/toluene. This material (0.37g, 1.4
mmol) was then stirred in methanol (20 ml) as thionyl chloride (2 ml) was cautiously
added. The suspension was stirred at reflux under argon for 2 days, and evaporated to
dryness. The residue was suspended in saturated sodium hydrogen carbonate solution, and
40 the solid was filtered off, washed with water, dried, and recrystallised from
ethanol/petroleum ether (b.p. 60-80° C), giving the title compound (0.16g, 41%) as a
white solid, m.p. 199-200° C.
- 17 -
wo 94/18170
PCT/EP94/00189
NMR CDMSOd6) 5 :
3.88 (3H, s). 6.98 (IH, dd. J 8. 2), 7.27 (IH, d, J 2), 7.34 (IH, dd, J 8, 5), 7.73 (IH, d, J
9), 7.96 (IH. m), 8.24 (IH, d, J 4), 8.63 (IH, d, J 2), 9.04 (IH, s), 9.27 (IH, s), 10.69 (IH,
s).
- 18 -
wo 94/18170
PCT/EP94/00189
Pharmacological data
[3H]-mesulergine binding to rat 5-HT2C clones expressed in 293 cells in vitro
Evidence from the literature suggests that 5-HT2C antagonists may have a number of
5 therapeutic indications including the treatment of ai.xiety, migraine, depression, feeding
disorders and obsessive compulsion disorders. (Curzon and Kenneit, 1990; Fozard and
Gray, 1989) and Alzheimer's Disease (Lawlor, 1989, J. Arch. Gen. Psychiat. Vol. 46
p.542).
10 The affinity of test drugs for the 5-HT2C binding site can be determined by assessing their
ability to displace [3H]-mesulergine from 5-HT2C clones expressed in 293 cells (Julius et
al., 1988). The method employed was similar to that of Pazos et al, 1984.
The cells suspension (50ml) was incubated with [^HJ-mesulergine (0.5nM) in Tris HCl
15 buffer (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in the
presence of mianserin (lO'^M). Ten concentrations of test drug (3 x 10'^ to
lO'^^M final concentration) were added in a volume of 50ml. The total assay volume was
5(X)ml. Incubation was stopped by rapid filtration using a Brandel cell harvester and
radioactivity measured by scintillation counting. The IC50 values were determined using
20 a four parameter logistic program (DeLean 1978) and the pKj (the negative logarithm of
the inhibition constant) calculated from the Cheng P*rusoff equation where:
Ki = IC50
25 1+ C
Kd
Kj = inhibition constant.
30 C = concentration of f 3H]-mesulergine
Kd = Affinity of mesulergine for 5-HTic binding sites.
Curzon. G.A. and Kennett, G.A. (1990). TIPS, Vol. 11, 181-182.
Fozard. J.R. and Gray, J.A. (1989). TIPS, Vol. 10, 307-309.
35 Pazos. A. et al. (1984). Eur. J. Pharmacol., 106, 531-538.
Julius eial. (1988) Science 241, 558-564
DeLean A, Munson P.J., Rodbaud D (1978) Am. J. Physiol 235, E97-E102.
- 19-
wo 94/18170
PCT/EP94/00189
Results
The compound of Example 7 has a pKi of 8.28.
The compound of Example 11 has a pKi of 7.79.
5 Reversal of MCPP-induced Hypolocomotion
Administration of m-(chlorophenyl)piperazine (mCPP) to rats induces hypolocomotion
(Kennett and Curzon 1988, Luckie et al. 1989) as seen with the related drug l-(m-
trifluoromethylphenyl)piperazine (TFMPP) fLucki and Frazer 1982, Kennett and Curzon
1988). This effect was blocked by the non specific
10 5-HT2C/5-HT2A receptor antagonists mianserin, cyproheptadine and metergoline and
perhaps by mesulergine. It was not blocked by the 5-HT2 receptor antagonists ketanserin
and ritanserin at relevant doses (Kennett and Curzon 1991) nor by antagonists of S-HTj^,
5-HTiB, 5-HT3, a2 adrenoceptors or dopamine D2 receptors. The effect of mCPP is
therefore considered to be mediated by 5-HT2C receptors (Kennett and Curzon 1988) as
15 confirmed by subsequent studies (Lucki ex al. 1989). Since mCPP causes
hypolocomotion when infused into the cerebral ventricles this effect is probably centrally
mediated (Kennett and Curzon 1988).
mCPP-induced hypolocomodon was measured in automated locomotion cages of
20 dimensions 56 cm long x WA cm wide x 25 cm high and made of black perspex. Two
photobeams traversed the width of the cages at either end at ground level. Sequential
breaking of these beams allowed the measurement of cage transits.
Male Sprague Dawley rats (200-250g) (Charles River) were housed in groups of six. They
25 were given drugs orally Ih pretest and 40 mins later mCPP (7 mg/kg i.p.). After a further
20 min they were placed in individual automated cages in groups of four under red light in
an adjacent room. After 10 min the test was terminated. Reversal of mCPP-induced
hypolocomotion was considered as evidence of in vivo central 5-HT2C receptor antagonist
properties.
30
Kennett, G.A., Curzon, G., (1988). Brit. J. Pharmacol. 94, 137-147.
Kennet G.A., Curzon, G., (1991). Brit.J. Pharmacol. 103, 2016-2020.
Lucki, I., Frazer, A., (1982) Am. Soc. Neurosci. 8(abstr.), 101.
Lucki, I., Ward, M.R., Frazer, A., (1989). J.Pharmacol. Exp. Therap. 249, 155-164.
35
Result
The compound of Example 1 1 had an ID50 of 78 mg/kg p.o.
- 20 -
wo 94/18170 PCT/EP94/00189
CLAIMS
1 . Use of a compound of formula (I) or a salt thereof:
2 3
R R
5
wherein:
P represents a quinoline or isoquinoline residue or a 5- or 6-membered aromatic
10 heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or
sulphur;
r1 is hydrogen, Ci.6 alkyl, halogen, NR5r6 or OR^ where R^, r6 and r''' are
independently hydrogen or Cj.^ alkyl;
r2 and r3 are independently hydrogen or Cj.g alkyl;
15 r4 is hydrogen, Ci.6 alkyl, CF3, nitro, cyano, acyl, halogen, NR5r6, OR^ or CO2R'''
where R^, and R'^ are independently hydrogen or Cj.g alkyl as defined for R^; and
n is 1, 2 or 3,
in the manufacture of a medicament for the treatment or prophylaxis of CNS disorders.
20 2. Use according to claim 1 in which P is pyridyl or quinolyl.
3. Use according to claim 1 or 2 in which r1 is hydrogen or methyl.
4. Use according to any one of claims 1 to 3 in which R^' and R^ are hydrogen.
25
5. Use according to any one of claims 1 to 4 in which P is pyridyl or quinolyl.
6. Use according to claim 1 in which the compound of formula (I) is selected from:
N-(Phenyl)-N'-(2-methyl-4-quinolinyl) urea,
30 N-(6-Quinolinyl)-N'-(3-trifluoromethylphenyl) urea,
N-(3-Dimethyiaminophenyl)-N'-(6-quinolinyl) urea,
N-(Phenyl)-N'-(6-quinolinyl) urea,
N-(4-Methoxyphenyl)-N'-(2-methy]-4-quinolinyl) urea,
N-(3-Dimethylaminophenyl)-N'-(2-methyl-4-quinolinyl) urea,
35 N-(3-Methoxyphenyl)-N'-(2-methyi-4-quinolinyl) urea.
- 21 -
wo 94/18170
PCT/EP94/00189
N-(3-Ethoxycarbonylphenyl)-N -(2-methyl-4-quinolinyl) urea,
N-(2-Methyl-4-quinolinyi)-N -(3-trifluoromethylphenyl) urea ,
N-(Phenyl)-N -(3-quinolinyl) urea,
N-(3-Chloro-4-methylphenyl)-N'-(3-pyridyl) urea,
5 N-(3-Chloro-4-methylphenyl)-N -(4-pyridyl) urea,
N-(3-Pyridyl)-N'-(3-(trifluoromethyl)phenyl)urea,
N-(3-Methylphenyl)-N'-(3-pyridyl)urea,
N-(4-Chlorophenyl)-N'-(3-pyridyl)urea,
N-(3-Chlorophenyl)-N'-(3-pyridyl)urea,
10 N-(3-Hydroxyphenyl)-N'-(2-methyl-4-quinolinyl)urea,
N-(3-Bromophenyl)-N'-(3-pyridyl)urea,
N-(3,4-Dichlorophenyl)-N'-(3-pyridyl)urea,
N-(3-Fluoro-4-methylphenyl)-N'-(3-pyridyl)urea,
N-(4-Ethoxycarbonylphenyl)-N'-(3-pyridyl)urea,
1 5 N-(3-Chloro-4-methoxycarbonylphenyl)-N'-(3-pjTidyl)urea,
N-(3-Bromo-4-methylphenyI)-N'-(3-pyridyI)urea,
N-(3-Chloro-4-cyanophenyI)-N'-(3-pyridyi)urea,
N-(4-Nitro-3-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(4-Chloro-3-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
20 N-(3-Chloro-4-carboxyphenyl)-N'-(3-pyridyl)urea,
N-(2-Methoxy-4-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-ethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-propylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-ten-butylphenyl)-N'-(3-pyridyl)urea,
25 N-('3-Hydroxy-4-(methoxycarbonyl)phenyl)-N'-(3-pyridyl)urea
or a pharmaceutically acceptable salt thereof.
7. A compound of formula (I) which is:
N-(PhenyI)-N'-(2-methyl-4-quino]inyl) urea,
30 N-(6-Quinolinyl)-N'-(3-trifluoromethylphenyl) urea,
N-C3-Dimethylaminophenyl)-N'-(6-quinolinyl) urea,
N-(Phenyl)-N'-(6-quinolinyl) urea,
N-(4-Methoxyphenyl)-N -(2-methyl-4-quinolinyl) urea,
N-(3-Dimethylaminophenyl)-N-(2-methyl-4-quinolinyl) urea,
35 N-(3-Methoxyphenyl)-N -(2-methyl-4-quinolinyl) urea,
N-(3-Ethoxycarbonylphenyl)-N -(2-methyl-4-quinolinyl) urea,
N-(2-Methyl-4-quinolinyl)-N -(3-trifluoromethylphenyl) urea ,
N-(Phenyl)-N -(3-quinolinyl) urea,
- 22 -
wo 94/18170
PCT/EP94/00189
10
15
20
25
30
N-(3-Chloro-4-methylphenyr)-N -(3-pyridyl) urea,
N-(3-Chloro-4-methYlphenyl)-N'-(4-pyridyl) urea,
N-(3-Pyridyl)-N'-(3-(trifluoromethyl)phenyl)urea,
N-(3-Methylphenyl)-M'-(3-pyridyl)urea,
N-(4-Chlorophenyl)-N'-(3-pyridyI)urea,
N-(3-Chlorophenyl)-N'-(3-pyridyl)urea,
N-(3-Hydroxyphenyl)-N'-(2-methyl-4-quinolinyl)urea,
N-(3-Bromophenyl)-N'-(3-pyridyl)urea,
N-(3,4-Dichlorophenyl)-N'-(3-pyridyl)urea,
N-(3-Fluoro-4-inethylphenyl)-N'-(3-pyridyl)urea,
N-(4-Ethoxycarbonylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-methoxycarbonylphenyl)-N'-(3-pyridyl)urea,
N-(3-Bromo-4-methylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-cyanophenyl)-N'-(3-pyridyl)urea,
N-(4-Nitro-3-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(4-Chloro-3-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(3-ChIoro-4-carboxyphenyl)-N'-(3-pyridyl)urea,
N-(2-Methoxy-4-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-ethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-propylphenyI)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-ten-butylphenyl)-N'-(3-pyridyI)urea,
N-(3-Hydroxy-4-(methoxycarbonyl)phenyl)-N'-(3-pyridyl)urea
or a pharmaceutically acceptable salt thereof.
8. A process for the preparation of a compound of formula (I) or a pharmaceutically
acceptable salt thereof which comprises:
the coupling of a compound of formula (II);
wherein P is as defined in relation to formula (I), A and B contain the appropriate
with a compound of formula (III);
(III)
- 23 -
wo 94/18170
PCT/EP94/00189
functional group(s) necessary to form the moiety, -NR^'CONR^' when coupled, the
variables R ^ , R^', r3', and R'^' are R ^ , R^, r3, and R^ respectively, as defined in formula
(I), or groups convenible thereto, and thereafter optionally and as necessary and in any
appropriate order, converting any R^', R^ , r3 and R^', when other than R^, R-^, R^ and
5 r4 respectively to R^, R^, R^ and R^, interconverting R^, r2, r3^ and R^ and forming a
pharmaceutically acceptable salt thereof.
- 24 -
INTERNATIONAL SEARCH REPORT
Ii al Application No
PCT/EP 94/00189
A. CLASSIFICATION OF SUBJECT MATTER . /- 1 1/ i >i
IPC 5 C07D213/75 C07D215/38 C07D215/46 A61K31/47 A61K31/44
According to International Patent Classificalion (IPC) or to both national clasnficaaon and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
IPC 5 C07D A61K
Documentaoon searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category °
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
Y
WO, A, 92 05170 (BEECHAM GROUP PLC) 2 April
1992
cited in the application
see the whole document
1-8
P.Y
WO, A, 93 18028 (SMITHKLINE BEECHAM PLC) 16
September 1993
*see whole document, especially definition
of P*
1-8
A
JOURNAL OF MEDICINAL CHEMISTRY
vol. 29, no. 11 , 1986 , WASHINGTON US
pages 2415 - 2418
P. FLUDZINSKI ET AL
' 2, 3-di al kyl (dimethyl ami no) i ndol es :
Interaction with 5HT1,5HT2 and rat stomach
fundal serotonin receptors.'
*see especially compound number 10*
-/--
1-8
Further documents are listed in the continuation of box C.
Patent family members are listed in annex.
° Special categones of cited documents :
"A' document defming the general state of the art which is not
considered to be of particular relevance
"E' earlier document but published on or after the international
filing date
"L" document which may throw doubts on priority claim(s) or
which is cited to establish the publication date of another
citation or other special reason (as specified)
'O' document referring to an oral disclosure, use, exhibition or
other means
■p' document published prior to the international filing date hut
later than the priority date claimed
"T' later document published after the international filing date
or priority date and not in conflict with the application but
cited to understand the principle or theory underlying the
invention
'X' document of particular relevance; the claimed invention
cannot be considered novel or caimot be considered to
involve an inventive step when the document is taken alone
'Y' document of particular relevance; the claimed invention
cannot he considered to involve an inventive step when the
doctanent is combined with one or more other such docu-
ments, such combination being obvious to a person skilled
in the art.
"&' document member <. ' the same patent family
Date of the actual completion of the international search
12 April 1994
Date of mailing of the international search report
OB. 05-3 It
Name and mailing address of the ISA
European Patent Office, P.B. 5818 Patentlaan 2
NL - 2280 HV Rijswijk
Tel. ( + 31-70) 340-2040, Tx. 31 651 epo nl,
Fax: (+31-70) 340-3016
Authorized officer
Scruton-Evans, I
Form PCT,aSA'210 (lecond sheet) (July 1992)
page 1 of 2
INTERNATIONAL SEARCH REPORT
Ii al Application No
PCT/EP 94/00189
C.(Continua&oii) DOCUMENTS CONSIDERED TO BE RELEVANT
Category °
Citation of document, with indication, where appropnate, of the relevant passages
Relevant to claim No.
A
A
A
P. A
EP.A.O 515 684 (CHUGAI SEIYAKU KABUSHIKI
KAISHA) 2 December 1992
*see compounds of formula I wherein R is
(I)-2, and their process of preparation on
page 8*
PATENT ABSTRACTS OF JAPAN
vol. 16, no. 473 (C-0991)2 October 1992
& JP,A,04 173 701 (HOKKO CHEM IND CO LTD)
22 June 1992
see abstract
US, A, 4 880 817 (R.M.KANOJIA ET AL) 14
November 1989
*see co1umn6, lines 64-68 and column 7,
lines 1-14*
EP,A,0 540 854 (SANSHO SEIYAKU CO. LTD.)
12 May 1993
*see compounds of formula 2 and
definitions of Rl and R2 on page 6*
EP,A,0 354 994 (TAKEDA CHEMICAL INDUSTRIES
LTD) 21 February 1990
1-7
1-7
1-7
1-7
1-8
Form PCTASA'210 (continuaUon of jecond sheet) (July 1992)
page 2 of 2
uiibrmation on patent family members
Ii il AppUcaaon No
PCT/EP 94/00189
Parent document
cited in search report
Publication
date
Patent family
member(s)
PnhHf*a tinn
I UUll«'0-Ul-'ll
date
WO-A-9205170
02-04-92
AU-B-
642041
07-10-93
AU-A-
8503891
15-04-92
CA-A-
2091246
14-03-92
EP-A-
0550507
14-07-93
JP-T-
6500551
20-01-94
NONE
AU-A-
WO-A-
7317391
9111994
03-09-91
22-08-91
WO-A-93 18028
EP-A-0515684
16-09-93
02-12-92
US-A-4880817
14-11-89
NONE
EP-A-0540854
12-05-93
AU-A-
CA-A-
2281792
2077850
11-03-93
11-03-93
EP-A-0354994
21-02-90
AU-B-
AU-A-
US-A-
JP-A-
616542
3802589
5254565
3007259
31-10-91
18- 01-90
19- 10-93
14-01-91
Form PCT/ISA/210 (patent famUy annex) (July 1992)